US4055641A

US4055641A - Method of treating benign prostatic hypertrophy

Info

Publication number: US4055641A
Application number: US05/684,945
Authority: US
Inventors: Harvey D. Benson; Joyce Francis Grunwell; John O'Neal Johnston; Vladimir Petrow
Original assignee: Richardson Merrell Inc
Current assignee: Richardson Vicks Inc
Priority date: 1976-05-10
Filing date: 1976-05-10
Publication date: 1977-10-25
Anticipated expiration: 1994-10-25
Also published as: ZA772087B; BE854414A; PH13959A

Abstract

Compounds of the following general formula are useful in treating benign prostatic hypertrophy: ##STR1## wherein R is --CHO or --CH₂ OR₁ ; each of R₁ and R₂ is hydrogen, alkylcarbonyl wherein the alkyl moiety has from 1 to 20 carbon atoms and is straight or branched, benzoyl, phenylalkylcarbonyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched or cycloalkylcarbonyl wherein the cycloalkyl moiety has from 5 to 10 carbon atoms; R₃ is hydrogen; or R₂ and R₃ together form a double bond between the 17-position carbon atom and the oxygen atom.

Description

FIELD OF INVENTION

This invention relates to methods of treating benign prostatic hypertrophy and pharmaceutical composition useful for said treatment.

BACKGROUND OF INVENTION

Benign prostatic hypertrophy or benign adenomatous hyperplasia is a common condition found in both man and animals. The condition in man is found most frequently in those over 60 years of age. Various modes of treatment are available including prostatectomy. Although surgical removal of the prostate provides an effective method of treatment in some patients such treatment is undesirable being considered a risky, unwanted or excessive mode of therapy. Although the etiology of benign prostatic hypertrophy is unknown it has been suggested that changes in the androgen-estrogen level with advancing age may account for the condition. Hormonal treatment of the patient has been investigated as a possible means of therapy including the use of estrogens, androgens and combinations of androgens-estrogens. Although such treatment has been reported to often result in improvement of the condition certain undesirable side effects also occur. For example, it is known that prolonged administration of estrogens to males can result in the occurrence of gynecomastia and impotence. Also, estrogens are known to interfere with blood clotting mechanisms resulting in thrombosis and stroke. The method provided by the present invention avoids the undesirable side effects associated with estrogen therapy.

Some of the compounds employed in this invention, for example, 19-hydroxyandrost-4-ene-3,17-dione and the 19-oxo derivative thereof have been involved in numerous in vitro studies wherein the role of the metabolism of androgens has been investigated. Additionally, 19-hydroxyandrost-4-ene-3,17-dione is reported to have been administered to two healthy male subjects each 21 years of age (J. Clin. Endocrinol. Metab. 28 1401 (1968))). Also, 3-oxo-17β-hydroxyandrost-4-ene-19-al has been reported in U.S. Pat. Nos. 3,235,573 issued Feb. 15, 1966, and 3,449,381 issued June 10, 1969, wherein the utilities disclosed are anabolic-androgenic activity, inhibition of pituitary gonadotrophins and adrenocorticotrophin, anti-estrogenic, blood, liver and adrenal cholesterol lowering properties, control of fertility and psychotic conditions, and appetite stimulants. To applicants' knowledge the use of the compounds employed in the present invention in the treatment of benign prostatic hypertrophy has not been taught or suggested heretofore.

SUMMARY OF INVENTION

This invention relates to a method of treating benign prostatic hypertrophy or benign adenomatous hyperplasia by administering a compound of the following general formula: ##STR2## wherein R is --CHO or --CH₂ OR₁ ; each of R₁ and R₂ is hydrogen, alkylcarbonyl wherein the alkyl moiety has from 1 to 20 carbon atoms and is straight or branched benzoyl, phenylalkylcarbonyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched or cycloalkylcarbonyl wherein the cycloalkyl moiety has from 5 to 10 carbon atoms; R₃ is hydrogen; or R₂ and R₃ together form a double bond between the 17-position carbon atom and the oxygen atom.

This invention also relates to pharmaceutical preparations suitable for use in treating benign prostatic hypertrophy.

DETAILED DESCRIPTION OF INVENTION

In the compounds of general Formula I the term alkylcarbonyl is taken to mean a group of the structure ##STR3## wherein the alkyl moiety has from 1 to 20 carbon atoms and is a straight chain or a branched chain. Illustrative examples of the alkyl moiety in the substituent alkylcarbonyl group are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, pivalyl, hexyl, heptyl, octyl, 2,4-dimethyloctyl, undecyl, 9-methylundecyl, pentadecyl, hexadecyl, dodecyl, 2,4,6-trimethyldecyl, heptadecyl, decyl, octadecyl, nonadecyl and didecyl.

The term benzoyl as used in reference to the compounds of general Formula I is taken to mean the group ##STR4##

The term phenylalkylcarbonyl as used in reference to the compounds of general Formula I is taken to mean a substituent group of the structure ##STR5## wherein the alkyl moiety, which may also be referred to as an alkylene moiety, has from 1 to 6 carbon atoms and is a straight chain or a branched chain. Illustrative examples of the alkyl moiety in the substituent phenylalkylcarbonyl group are methyl, ethyl, n-propyl, n-butyl, n-pentyl, hexyl, isopropyl, sec-butyl, tert-butyl and neopentyl.

Illustrative example of cycloalkylcarbonyl groups which R₁ and R₂ may be are cyclopentanecarbonyl, cyclohexanecarbonyl, cyclooctanecarbonyl, 1- or 2-norbornanecarbonyl, and 1- or 2-adamantanecarbonyl.

It is apparent from the foregoing general Formula I that the compounds employed in the instant invention are androst-4-ene-3,17-diones having a --CH₂ OR₁ or --CHO group at the 10β-position as represented respectively by the following general Formulas II and III, or are 17β-hydroxyandrost-4-en-3-one derivatives or esters thereof as defined by R₂ having a --CH₂ OR₁ or --CHO group present at the 10β-position as represented respectively by the following general Formulas IV and V: ##STR6##

In general Formulas II and IV R₁ is hydrogen or alkylcarbonyl wherein the alkyl moiety has from 1 to 20 carbon atoms and is straight or branched, benzoyl, phenylalkylcarbonyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched or cycloalkylcarbonyl wherein the cycloalkyl moiety has from 5 to 10 carbon atoms as defined hereinabove.

In general Formulas IV and V the hydrogen atom attached to the 17- position is in the alpha position, and R₂ is hydrogen or alkylcarbonyl wherein the alkyl moiety has from 1 to 20 carbon atoms and is straight or branched, benzoyl, phenylalkylcarbonyl or cycloalkylcarbonyl as defined hereinabove.

The use of the compounds as represented by each of general Formulas II and III in the treatment of benign prostatic hypertrophy of the compounds of general Formula III represents a more specifically preferred embodiment of this invention. Other embodiments of this invention are the use of the compounds as represented by general Formulas IV and V in the treatment of benign prostatic hypertrophy with the use of the compounds of general Formula IV wherein R₁ and R₂ each represent hydrogen and the compounds of general Formula V wherein R₂ represents hydrogen being more preferred embodiments.

Illustrative examples of compounds employed in the present invention are 17β,19-bis-(1-oxopropoxy)androst-4-en-3-one, 17β,19-bis-(1-oxodidecyloxy)androst-4-en-3-one, 17β,19-dihydroxyandrost-4-en-3-one, 19-hydroxy-17β-(1-oxopropoxy)androst-4-en-3-one, 19-hydroxy-17β-(1-oxohexadecyloxy)androst-4-en-3-one, 19-acetoxyandrost-4-ene-3,17-dione, 19-acetoxy-b 17β-hydroxyandrost-4-en-3-one, 3-oxo-17β-hydroxyandrost-4-en-19-al, 19-(1-adamantanylcarbonyloxy)androst-4-ene-3,17-dione, 19-(1-norbornylcarbonyloxy)androst-4-ene-3,17-dione, 19-(1-cyclopentylcarbonyloxy)androst-4-ene-3,17-dione, 3,17-dioxoandrost-4-en-19-al and 3-oxo-17β-(1-adamantanylcarbonyloxy)-androst-4-en-19-al.

The compounds employed in the present invention can be administered to a patient in need thereof in various manners to achieve the desired effect. The compounds can be administered alone or in the form of pharmaceutical preparations to the patient being treated either orally or parenterally, that is, subcutaneously and intramuscularly, including injection of the active ingredient directly into the prostate. The amount of compound administered can vary over a wide range to achieve the desired effect and will vary with the mode of administration, for example, smaller dosages may be required when the active ingredient is injected directly into the prostate than when the active ingredient is administered orally. The amount of compound administered can vary from about 0.1 to about 500 mg/kg and preferably from about 0.1 to 250 mg/kg. These dosage ranges represent the amount of compound that will be effective in reducing the size of the hypertrophied prostate, that is, the amount of compound that is effective in treating prostatic hypertrophy. For parenteral administration and particularly for injection of the active ingredient directly into the prostate gland a lesser dose, for example, from 0.1 to 25 mg/kg may be used.

As used herein the term patient is taken to mean a warm blooded male mammal, for example, man, dogs, or rodents having benign prostatic hypertrophy. As used herein the term benign prostatic hypertrophy is not intended to include prostatitis, that is, inflammation of the prostate due to, for example, a bacterial infection.

For oral administration the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, powders, solutions, suspensions or emulsions. The solid unit dosage forms can be of the conventional type. Thus, the solid form can be a capsule which can be of the ordinary gelatin type containing a compound of general Formula I and a carrier, for example, lubricants and inert filler such as lactose, sucrose, and cornstarch. In another embodiment the compounds of general Formula I can be tableted with conventional tablet bases such as lactose, sucrose and corn starch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents such as potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate.

For parenteral administration the compounds may be administered as injectable dosages of a solution or suspension of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid such as water and oils with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants. Illustrative of oils which an be employed in these preparations are those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, and mineral oil. In general water, saline, aqueous dextrose, and related sugar solutions, ethanols and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.

The compounds can be administered in the form of a depot injection or implant preparation which may be formulated in such a manner as to permit a sustained release of the active ingredient. The active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants. Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber manufactured by the Dow-Corning Corporation.

Following are illustrative pharmaceutical formulations which may be employed in practicing the present invention:

______________________________________                                    
Tablet                   For 15,000                                       
______________________________________                                    
3,17-Dioxoandrost-4-en-19-al                                              
                         2.625 Kg                                         
Fine Powder                                                               
Lactose                  6.750 Kg                                         
Corn Starch              0.563 Kg                                         
______________________________________

Mix the active ingredient, the lactose and corn starch uniformly. Granulate with 10% starch paste. Dry to a moisture content of about 2.5%. Screen through a No. 12 mesh screen. Add and mix the following:

______________________________________                                    
Magnesium Stearate       0.225 Kg                                         
Corn Starch qs ad        11.250 Kg                                        
______________________________________

Compress on a suitable tablet machine to a weight of 0.750 g/tablet.

Soft Gelatin Capsule

______________________________________                                    
3,17-Dioxoandrost-4-en-19-al                                              
                         0.25 Kg                                          
Polysorbate 80           0.25 Kg                                          
Corn Oil qs ad           25.0  Kg                                         
______________________________________

Mix and fill into 50,000 soft gelatin capsules.

IM Depot Injection

______________________________________                                    
3,17-Dioxoandrost-4-en-19-al                                              
                         5 mg                                             
micronized                                                                
Dimethylsiloxane         240 mg                                           
Catalyst qs                                                               
______________________________________

Disperse the drug substance in the fluid dimethylsiloxane. Add the catalyst and cast into a suitable monolytic structure.

Alternatively, the drug substance may be enclosed by a pre-cast polydimethylsiloxane envelope. Alternatively, the drug substance may be dispersed in a suitable amount of hydroxyethyl acrylate subsequently poymerized and crosslinked by the addition of ethylenedimethacrylate, and an oxidizing agent, to yield a 3-dimensional ethylene glycomethacrylate mouldable gel (Hydron).

Injections

A. Oil Type

______________________________________                                    
3,17-Dioxoandrost-4-en-19-al                                              
                          25 mg                                           
BHA, BHT (of each         0.01% w/v                                       
Peanut Oil or Sesame Oil qs                                               
                          1.0 ml                                          
______________________________________

B. Suspension Type

______________________________________                                    
3,17-Dioxoandrost-4-en-19-al                                              
                          25 mg                                           
Sodium Carboxymethylcellulose                                             
                          0.5% w/v                                        
Sodium Bisulfite          0.02% w/v                                       
Water for injection, qs   1.0 ml                                          
______________________________________

Buccal or Sublingual Tablet

______________________________________                                    
3,17-Dioxoandrost-4-en-19-al                                              
                          1%                                              
Calcium Stearate          1%                                              
Calcium Saccharin         0.02%                                           
Granular Mannitol         qs                                              
______________________________________

Mix and compress on a suitable tablet machine to a weight of 0.115 g/tablet.

Administration of the compounds of general Formulas I to V to a patient in need thereof in the effective amounts described hereinabove provides an effective method of treating benign prostatic hypertrophy without the occurrence of certain deleterious side effects known to occur with the administration of estrogenic agents including thrombotic effects, such as blood clotting and feminizing effects such as gynecomastia and male impotence. Administration of the compounds employed in the present invention in amounts higher than the amount specified above as an effective amount may result in these deleterious estrogenic side effects.

To demonstrate the activity of the compounds employed in the present invention immature intact male Sprague-Dawley rats 23 days of age were treated parenterally with the test compound for ten days. The drug effect on gonadal accessory organs was demonstrated by determining the relative organ weight on the eleventh day of treatment. When 3,17-dioxoandrost-4-en-19-al is administered as the test compound ventral prostate weight was significantly reduced when compared with vehicle treated controls as demonstrated by the data contained in the following Table I.

              TABLE 1                                                     
______________________________________                                    
Inhibition of Prostatic Growth                                            
        Dose      No.     Prostate Wgt.*                                  
                                    % of                                  
Treatment                                                                 
        mg/kg/day Rats    (mg ± S.E.M.)                                
                                    Control                               
______________________________________                                    
Vehicle --        10      67.5 ± 5.4                                   
                                    100                                   
3,17-Dioxo-                                                               
        50        6       40.0 ± 4.4**                                 
                                    59                                    
androst-4-                                                                
en-19-al                                                                  
______________________________________                                    
  *Relative organ weight, mg/100 g body weight                            
  **Significantly different from vehicle controls, p ≦ 0.01

The effectiveness of the compounds employed herein has also been demonstrated in dogs. An aged beagle dog was diagnosed by way of rectal palpation to have an enlarged prostate. Pathological examination of a pretreatment prostate biopsy confirmed hyperplasia and prostatitis. Dimethylpolysiloxane implants containing micronized crystalline 3,17-dioxoandrost-4-en-19-al prepared to deliver an estimated 300 to 500 μg/24 hours were implanted. After seven months of therapy a second prostatic biopsy was performed at which time the prostate was approximately one-fourth the size seen at the first examination and neither prostatitis nor hyperplastic cells were seen in the tissues examined confirming the effectiveness of the compound.

It has also been found that the compounds employed in the present invention have a markedly reduced thrombotic potential as compared to estrogens. For example, 3,17-dioxoandrost-4-en-19-al was given subcutaneously to ovariectomized albino rats for seven days at either 0.1 or 3.0 mg/kg. Body weight and uterine weights were measured. Blood samples were taken and the effect on thrombotic potential determined through measurements of anti-thrombin III activity, ethanol gel tests, (fibrin monomer level), protamine sulfate test (fibrin degradation product), adenosinediphosphate and collagen induced platelet aggregation. Anti-thrombin activity was not affected nor was increased fibrin monomer or fibrin degradation product level detected. Platelet aggregation was not significantly changed.

Many of the compounds employed in the present invention are known in the art or are commercially available. For example, 19-hydroxyandrost-4-ene-3,17-dione, 17β,19-dihydroxyandrost-4-en-3-one, 19-hydroxy-17β-(1-oxoethoxy)-androst-4-en-3-one, 19-hydroxy-17β-(1-oxobenzyloxy)androst-4-en-3-one and 3-oxo-17β(1-oxobenzyloxy)androst-4-en-19-al are commercially available.

The esters of the compounds employed in the present invention, that is, compounds wherein either or both of R₁ and R₂ are alkylcarbonyl wherein the alkyl moiety has from 1 to 20 carbon atoms and is straight or branched, cycloalkylcarbonyl wherein the cycloalkyl moiety has from 5 to 10 carbon atoms, benzoyl and phenylalkylcarbonyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched can be prepared as follows although other methods may also be employed. Ester derivatives of 19-hydroxyandrost-4-ene-3,17-dione and bis-ester derivatives of 17β,19-dihydroxyandrost-4-en-3-one are prepared by reacting the corresponding 19-hydroxy or 17β,19-dihydroxy compound with an appropriate acid anhydride of the formula ##STR7## or acid chloride of the formula a ##STR8## wherein R₄ is an alkyl group of from 1 to 20 carbon atoms and is straight or branched, a cycloalkyl group of from 5 to 10 carbon atoms, phenyl or phenylalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched in the presence of a base such as pyridine, quinoline or trialkylamine, such as, triethylamine, which base serves as the solvent, for from 1 to 24 hours at a temperature of from about 25° to 100° C. The appropriate acid anhydride or acid chloride are known in the art or can be prepared from the corresponding acids by procedures well known in the art.

Compounds employed in the present invention wherein R₁ is hydrogen and R₂ forms an ester group are prepared from the above obtained 17β,19-diester derivatives by refluxing the diester with one equivalent of sodium bicarbonate or potassium bicarbonate or one-half equivalent of sodium carbonate or potassium carbonate or dilute sodium hydroxide or potassium hydroxide solution in a lower alcohol solent such as methanol or ethanol and water for about one hour, the reflux temperature depending on the solvent system employed.

Compounds employed in the present invention wherein R is CHO and R₂ forms an ester group are prepared by dissolving the above obtained compounds wherein R₁ is hydrogen and R₂ forms an ester group in acetone cooled to 0° to 10° C. and treating the solution with sufficient Jones reagent to effect the oxidation. Jones reagent is prepared by standard procedures using 26.72 grams of chromium trioxide, 23 ml of concentrated sulfuric acid and water to make 100 ml. The Jones reagent can be added to the solution until the reddish brown color persists which requires about 289 ml. Other oxidizing agents can be used, such as, dicyclohexylcarbodiimide in dimethylsulfoxide.

The following specific examples further illustrate the preparation of compounds employed in the instant invention.

EXAMPLE 1 17β,19-Bis(1-oxopropoxy)androst-4-en-3-one

A solution of 10 g of 17β, 19-dihydroxyandrost-4-en-3-one which is commercially available and 25 ml of propionic anhydride in 200 ml of pyridine is allowed to stand overnight after which 100 ml of ethanol is added, and the reaction mixture is stirred for 1 hour. The mixture is then poured into 1 liter of water and the solid product is collected by filtration. The solid is dissolved in ether, dried over magnesium sulfate, filtered and the solvent removed. The residue is dissolved in hot hexane and allowed to cool yielding 17β,19-bis(1-oxopropoxy)androst-4-en-3-one. M.P. 82°-84° C.

EXAMPLE 2 17β,19-Dihydroxyandrost-4-en-3-one

A solution of 150 g of 19-hydroxyandrost-4-en-3-one in 6 liters of ethanol is cooled in an ice bath. To this cold solution is added 13.5 g of potassium borohydride, and the reaction mixture is stirred for two hours at about 0 ° C after which a second 13.5 g or potassium borohydride is added. Two hours later a third 13.5 g portion of potassium borohydride is added to the reaction mixture which is stirred for an additional 1 hour then poured into 11 liters of water which 70 ml of acetic acid is added. The ethanol is distilled off under reduced pressure and the aqueous residue cooled to 0° C. The solid which separates is filtered off, dried and dissolved in 25 liters of hot chloroform after which the temperature is adjusted to 25° C. To the chloroform solution is added 250 g of manganese dioxide, and the mixture is stirred for 2 hours then filtered and the solvents removed under reduced pressure. The solid residue is recrystallized from acetonitrile to give 17β,19-dihydroxyandrost-4-en-3-one. M.P. 205°-207° C.

EXAMPLE 3 19-Hydroxy-17β(1-oxopropoxy)androst-4-en-3-one

A solution of 11 g of 17β,19-bis(1-oxopropoxy)androst-4-en-3-one in 2 liters of methanol is treated with 2.5 g of sodium carbonate in 250 ml of water and refluxed for one hour after which the reaction mixture is poured into 10 liters of water, and the solid collected by filtration. The solid is dissolved in methylene chloride, dried over magnesium sulfate, filtered and the solvent removed. The residue is crystallized from acetone-hexane yielding 6 g of 19-hydroxy-17β(1-oxopropoxy)androst-4-en-3-one. M.P. 160°-162° C.

EXAMPLE 4 19-Acetoxyandrost-4-ene-3,17-dione

A solution of 19-hydroxyandrost-4-ene-3,17-dione in acetic anhydride and pyridine is allowed to stand overnight after which the reaction mixture is poured into ice water. The resulting solid is collected, dried and recrystallized from hexane to give 19-acetoxyandrost-4-ene-3,17-dione.

EXAMPLE 5 19-Acetoxy-17β-hydroxyandrost-4-en-3-one

To a solution of 25.6 g of 19-acetoxyandrost-4-ene-3,17-dione in 4 liters of methanol cooled to 0° C is added 3.1 g of sodium borohydride, and the mixture is stirred at 0° C for 1 hour after which 30 ml of acetic acid is added and the methanol removed under reduced pressure. The resulting residue is taken up in ethyl acetate and washed with water. The organic layer is dried over magnesium sulfate, filtered and the solvent removed. The solid residue is dissolved in 2 liters of chloroform treated with 125 g of manganese dioxide and stirred for 2 hours. The reaction mixture is filtered, and the solvent removed under reduced pressure. The residue is chromatagraphed on alumina using benzene-ether (1:1) as the eluant. The product is recrystallized from acetone-hexane to give 19-acetoxy-17β-hydroxyandrost-4-en-3-one, M.P. 125°-127° C.

EXAMPLE 6 19-Hydroxy-b 17β(2'-tetrahydropyranyloxy)androst-4-en-3-one

To a solution of 10 g of 19-acetoxy-17β-hydroxyandrost-4-en-3-one in 300 ml of dihydropyran is added a small crystal of p-toluene sulfonic acid. The reaction mixture is allowed to stand overnight after which it is dissolved in ether and extracted with dilute sodium bicarbonate. The ether layer is dried over magnesium sulfate, filtered and the solvent removed. The resulting residue is dissolved in 2 liters of methanol and 2.5 g of sodium bicarbonate in 250 ml of water is added. The methanol solution is refluxed for one hour after which the solvent is removed under reduced pressure at 40° C. The residue is covered with water, and the solid crude product collected and recrystallized from ethylacetate yielding 19-hydroxy-17β(2'-tetrahydropyranyloxy)androst-4-en-3-one. M.P. 193°-199° C.

EXAMPLE 7 3-Oxo-17β-hydroxyandrost-4-en-19-al

A solution of 7 g of 19-hydroxy-17β-(2'-tetrahydropyranyloxy)androst-4-en-3-one in 500 ml of acetone is cooled to 10° C and 5.3 ml of Jones reagent is added dropwise. The reaction is stirred for an additional 10 minutes then poured into water and extracted with ethylacetate. The ethylacetate extract is dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue is dissolved in 250 ml of 95% ethanol and 2 ml of concentrated hydrochloridic acid is added. The ethanol solution is refluxed for one hour then cooled to room temperature and neutralized with solid sodium carbonate. The neutralized solution is diluted with water and extracted with ethyl acetate. The extract is dried over magnesium sulfate, filtered and the solvent removed leaving a residue which is chromatagraphed on alumina using 25% ether in benzene as the eluant to give the product 3-oxo-17β-hydroxyandrost-4-en-19-al, M.P. 125°-127° C.

EXAMPLE 8 19-(1-Adamantanylcarbonyloxy)androst-4-ene-3,17-dione

A solution of 22 g of 19-hydroxyandrost-b 4-ene-3,17-dione, 18 g of 1-adamantanecarboxylic acid chloride and 29 ml of pyridine in 2.2 liters of toluene is refluxed overnight. The reaction mixture is cooled, and the toluene layer is washed with water, dried over magnesium sulfate and filtered then the solvent is removed. The resulting residue is crystallized from methanol to give 19-(1-adamantanylcarbonyloxy)androst-4-ene-3,17-dione, M.P. 161°-163° C.

EXAMPLE 9 3,17-Dioxoandrost-4-en-19-al

To a solution of 30 g of 19-hydroxyandrost-4-ene-3,17-dione in 3 liters of acetone cooled in an ice bath is added 28 ml of Jones reagent over a 1 hour period. The reaction mixture is stirred for an additional 15 minutes, filtered and the solvent removed under reduced pressure at 35° C. The residue is taken up in a large volume of ether and 1.5 liters of water. The ether layer is collected, dried over magnesium sulfate, filtered and the solvent removed. The residue is crystallized from acetone-hexane to give 3,17-dioxoandrost-4-en-19-al, M.P. 126°-129° C.

EXAMPLE 10 3-Oxo-17β-(1-oxopropoxy)androst-4-en-19-al

To a solution of 14 g of 19-hydroxy-17β-(1-oxopropoxy)androst-4-en-3-one in 1 liter of acetone cooled in an ice bath is added 13.3 ml of Jones reagent over one hour after which the reaction mixture is poured into a large volume of water and extracted with ether. The ether extract is dried over magnesium sulfate, filtered and the solvent removed. The residue is crystallized from acetone-hexane to give 3-oxo-17β(1-oxopropoxy)androst-4-en-19-al, M.P. 119°-121° C.

Claims

We claim:

1. A method of treating benign prostatic hypertrophy in a patient in need thereof which comprises administering to said patient an effective amount of a compound of the formula: ##STR9##wherein R is --CHO or --CH₂ OR₁ ; each of R₁ and R₂ is hydrogen, alkylcarbonyl wherein the alkyl moiety has from 1 to 20 carbon atoms and is straight or branched, benzoyl, phenylalkylcarbonyl wherein th alkyl moiety has from 1 to 6 carbon atoms and is straight or branched or cycloalkylcarbonyl wherein the cycloalkyl moiety has from 5 to 10 carbon atoms; R₃ is hydrogen; or R₂ and R₃ together form a double bond between the 17- position carbon atom and the oxygen atom.

2. The method of claim 1 wherein the compound is administered in an amount of from 0.1 to 500 mg/kg.

3. The method of claim 2 wherein the compound is administered orally.

4. The method of claim 1 wherein the compound is administered in an amount of from 0.1 to 250 mg/kg.

5. The method of claim 4 wherein the compound is administered orally.

6. The method of claim 4 wherein the compound is administered parenterally.

7. The method of claim 1 wherein R is --CHO.

8. The method of claim 7 wherein R₂ and R₃ together form a double bond between the 17- position carbon atom and the oxygen atom.

9. The method of claim 8 wherein the compound is 3,17-dioxoandrost-4-en-19-al.

10. The method of claim 1 wherein R is --CH₂ OR₁.

11. The method of claim 10 wherein R₂ and R₃ together form a double bond between the 17- position carbon atom and the oxygen atom.

12. The method of claim 11 wherein the compound is 19-hydroxyandrost-4-en-3,17-dione.